Bone metabolism Flashcards
1
Q
Where is calcium in the body?
A
- 99% sequested in bone
- 1% in extracellular fluid
2
Q
What is calcium important for ?
A
- Bones
- nerve
- muscle
- hormone function
- clotting
3
Q
A
4
Q
what is plasma calcium found as?
A
- 50% bound to albumin
- 50% free
- maintained at level 2.2-2.6mmol/L
5
Q
Where is the calcium absorbed from?
A
- The dudodenum
- by active transport
- mediated by calcium- binding protein and ATP
- regulated by 1,25 dihydroxycholcalciferol (1,25 (OH)2- vitamin D3 via passive diffusion by the jejunum
6
Q
What precentage of calcium filtered by kidneys is reabsorbed?
where does this occur?
A
- 99%
- 60% in proximal convoluted tubules
7
Q
Where is phosphate found?
A
- 85% stored in bone
- functions as metabolite and buffer in enzyme systems
- circulates unbound in plasma
- daily requirement is 1-1.5g/day
- dietary intake is usually sufficient
8
Q
What is the recommended intake of calcium for children/ 10-25 yrs, 25-65yrs, lacation, post menopause females?
A
- CHildren 600 mg/day
- 10-25 yrs 1400 mg/day
- 25-65 yrs 750 mg/day
- lactation 2000 mg/day
- post menopausal female 1500 mg/day
9
Q
How is vitamin D obtained?
what is its role?
A
- Naturally occuring steriods are ingested from fish oils and plants
- activated by skin by UV light
- they enhance calcium and phosphorous absorption across the small intestine via promotion and synthesis of calcium transporting protein and enhance osteoclastic resorption from bone , increasing serum **levels of calcium and phosphate **
- vitamin D also inhibits PTH
10
Q
How does the activation process of vitamin D occur?
A
- UV light-> transforms 7 dehydrocholestrol to cholecalciferol ( vitamin D3)
- hydroxylated in liver -> 25 hydroxycholecalciferol ( 25(OH) vitamin D3)
- serum 25 hydroxycholecalciferol is the most accurate indicator of body vitamin D stores
- further hydroxylation of 25 hydroxycholecalciferol occurs in mitochondria of proximal convulted tubular cells of kidney-> 1.25 dihydroxycholcalciferol ( 1.25(OH)2- vitamin D3- active form of vitamin D
11
Q
What activated vitamin D metabolism?
A
- Low serum calcium/ phosphate
- High PTH
12
Q
What happens to vitamin D when there is low levels of PTH or increased levels of CA/Po4?
A
- Convserion of active 1,25 dihydroxycholecalciferol to inactive 24,25( OH)2 vitamin D3
13
Q
What is parathyroid hormone?
A
- 84 amino acid peptide
- secreted by chief cells of the 4 parathyroid glands in the response to changes in EC calcium via calcium sensing receptor
14
Q
When in PTH secreted?
A
- In response to decreased serum calcium/phosphate
15
Q
When is PTH inhibited by?
A
- elevated serum calcium
- elevated 1,25 dihydroxylcalciferiol
16
Q
What is PTH actions in the kidney?
A
- Stimulate of hydroxylation of 25 hydroxycalciferol 25(OH)- vitamin D3, in the proximal tubules-> indirect intestinal effects
- increased reabsoption of filtered calcium in the kidney
- promotion of urinary excretion of phosphate from kndney
17
Q
What is PTH actions in the bone?
A
- stimulates osteoclasts
- stimulates precursors
- -> bone reabsorption
18
Q
What is PTH overall effect?
A
- Serum calcium levels are increased and phosphate levels are decreased
19
Q
What is calcitonin?
A
- 32 aminoacid peptide
- secreted by the parafollicular C cells of Thyroid gland
20
Q
When is Calcitonin secreted?
A
- In reponse to elevated serum calcium
21
Q
When is calcitonin inhibited?
A
- by decreased serum calcium
22
Q
What does calcitonin do?
A
- Directly inhibits osteoclasts ( have calcitonin receptors
23
Q
What are calcitonin effects?
A
- Include reduction of cellular motility
- retraction of cytoplasmic extensions
- reduction of ruffled osteoclast border
- this produces a transient decrease in serum calcium
24
Q
What is the effect of oestrogen?
A
- Inhibits bone reasorption and therefore prevents bone loss
- also inhibits bone formation
- does not increase bone density
25
What is the effect of corticosteriods on bone?
* **Reduce GI absorption**
* **increase renal excretion of calcium** thus inhibiting bone matrix formation-\> **hyperparathyroidism**-\> **rapid bone loss**
* pts on corticosteriods should be given calcium and vitamin D with or without bisphosphonates
26
What do thyroid hormones have on the bone?
* **Increase bone turnover**
* favouring bone absorption ( seen in hyperthyroidism)
27
What do growth hormones do to bone?
* Produce a positive calcium balance by **increasing gut absorption**
28
What does insulin do to bone loss?
* Type i if poorly controlled may lead to bone loss
29
What do growth factors IL1, IL6 TNF alpha, IGF & TGF do to bone loss?
* **IL1, IL-6 , TNF alpha stimulate proliferation** of osteoclast precursors
* **IGF activates osteoblasts**, produced by osteoblasts
* **TGF activates osteoblasts,** also stimulates osteoclastic precursors in vitro
30
What happens to bone mass with age?
* **Increases** up to a peak between **16-25yrs**
* after this there is a **normal phsyiological loss of bone mass** over time for both men and women of **0.3-0.5 % per year**
* thus calcium balance is positive in the first decades of life after which it becomes negative
* women have an increase in bone loss up to **2-3% at the menopause** but **after the first menopausal decade the rate of bone loss is equivalent for both men and women**
31
What is bone's 3 main function?
* **primary reservoir of calcium**
* **Haemopoietic marrow**
* located in cancellous bone supplies the body's cells. tissues and organs with erythrocyte, leukocytes and platelets
* Bone has a **mechanical role** in supporting the body's tissues
32
What is woven bone?
* collagen fibres are aligned **randomly**
* no lamellae-\> bone weaker
* more flexible
* **isotrophic characteristics-** uniform properties in all directions
33
Where is woven bone found?
* Embryonic/ Neonatal skeleton
* metaphyseal region of growing bones
* fx callus of children
* absent in normal adult but appears in **hard callus** following fx
* also found in pathological fx- **Pagets/osteogenesis imperfecta**
34
What forms cortical and cancellous bone?
* **Lamellar** ( mature) bone
* with **stress orientated fibres**
* leads to an **aniostrophic characteristic**
35
What cells lay down lamella bone?
* Osteoblasts
36
Within each lamella what do the collagen fibres do?
* Run at oblique angles to each other- **herring bone**
* **Cement lines** separate the lamella
37
What is lamella bone composed of?
* predominantly a matrix with a small population of **osteocytes** ( trapped osteoblasts) encased within bony **lacunae** and resting **bone lining cells** ( with osteoblastic potential) covering the bony surfaces
38
Decribe cortical bone?
* **80% of adult skeleton**
* lamella laid down in concentric rings-\> tubular lamellar systems= **osteons/Haversian systems**
* **approx 50um diameter**
* **individual osteons are aligned along lines of force** (usually parallel with the long axis of the bone)
* each osteon has a **central haversian canal surrounded by 5-7 concentric rings of lamella**
* **cement lines- separate osteons**
39
How do the osteocytes within the osteons communicate?
* Via gap junctions within channels = **canaliculi**
40
What is the name of the second set of canals that penetrate the cortical bone?
what is there function?
* **Volkmann's canal**
* run **perpendicular to the long bone axis** connecting inner an outer surfaces of bone
* canals carry **blood vessels to and from the haversian system**
41
What is the young's modulus of cortical bone?
* YM 20GPa cf cancellous 1GPa
* cortical bone is more resistant to bending and torsion
* Denser
42
Where is cancellous bone found?
* metaphysis and epiphysis of long bones
* centrally in cuboid bones
43
What is the structure of cancellous bone?
* **3d lattice of interconnecting tabeculae** which are alignes along axis of mechanical stress, enclosing elements of the bone marrow
* each of the trabeculae is made up of parallel sheets of **lamella**
* **osteocyte****s, lacunae adn canaculi similar to cortical bone**
* **_No haversian systems_**
* **x8 turnover rate of cortical bone** due to large surface area
* less dense, less elastic, brittle& less strong than cortical bone
44
Describe the layers of the periosteum?
* **Inner cambial layer- loose, vascular , oseogenic**
* **outer fibrous layer**- **more structural, less cellular** and **continuous with joint capsules**
* with age the periosteum thins adn has less osteogenic potential
45
What is bone?
* Composite materal consisting of cells 10% and matrix 90% that has inorganic and organic compotents
46
Describe the cells of bone?
* **Osteoblasts**
* **Osteocytes**
* **Bone lining cells**
* **Osteoclasts**
47
What are osteoblasts?
* from **Undifferentiated Mesenchymal stem cells** in marrow
* Produce **osteoid** ( bone forming cells) - contains type 1 collagen, deposied in pre-exisiting mineralised surfaces
* Have great **Synthetic capacity** ( abundant rough endoplasmic reticulum, golgi apparatus and mitochondria)
* show **high alkaline phosphatase activity**
* mediated by bone morphogenic proteins,growth factors and cytokines
* 3 fates
* become **inactive bone - lining cells**
* surround with matrix-\> **osteocytes**
* undergo **apoptosis**
48
What are osteocytes?
* **osteoblasts that become entrapped by calcified bone matrix**
* **90%** of bone cell population
* interconnect via **long cytoplasmic processes** in the canaliculi
* important in **controlling calcium** and **phosphorous metabolism-** respond to PTH/Calcitonin/ mechanical and electrical potential
49
What are bone lining cells?
* Flat cells lying on the surface of the bone possess **cytoplasmic extensions** that pentrate bone matrix & **communicate with osteocytes**
* **Inactive osteoblasts **that may be reactivated to become osteoblasts
* **Gatekeeper function**: when stimulated by PTH, they undergo cyclic adenosine monophosphate (cAMP) mediated morphological changes that expose the bone surface and _allow osteoclasts to start resorption_
50
What are osteoclasts?
* Mononuclear osteoclast precursor cells (**preosteoclasts**) arise from **haematopoietic _macrophage_ and _monocyte stem-cell line_**
* found in marrow and circulating blood
* _When stimulated_ these cells _proliferate & fuse_ -\> **large multinucleated osteoclast**
* **typically 3-20 nuclei,** large no of mitochondria and lyosomes that produce **acid phosphatase**
* osteoclasts reabsorb bone _within pits_ **= Howship's lacunae** on endosteal/periosteal surface of bone
* **Ruffles ( brush) border** that increases surface area which binds to bone surface via **Integrins**, sealing the area
* A **low pH** is produced beneath this area ( via _carbonic anhydrase system, adenosine triphosphate dependent proton pumps and the Na/H+ exchange system_ which dissolves the inorganic apatite crystals
* _Acid protelytic lysosomal enzymes_, such as tartrate-resistant isoenzyme of acid phosphatase ( **TRAP**) and cysteine proteinases such as **cathepsin** then hydrolyse the organic matrix components
* In dense _cortical bone_, OC lead **cutting cones** that tunnel thru the bone creating resorption cavities
* control of OC is related to OB
51
What is a bone remodelling unit?
* is an **area of remodelling by a set of osteoblasts. osteoclasts and stromal supporting tissue**
* in normal bone formation matches resorption with continual turnover of bone
* osteoclast precursors are activated -\> osteoclasts which reabsorb bone
* this is followed by reversal , whereby osteblast precursors are activated to form osteoblasts which lay down osteoid, which undergoes mineralisation to form bone
52
What does the bone matrix consist of?
* **Inorganic matrix 60% -** resists **compression forces**
* **Organic matrix 40% -** resists **tensile forces**
53
What is the inorganic matric composed of?
* **Calcium phosphate crystals** analogous to **calcium hydroxyapatite**
* **Ca10 ( PO4)6(OH)2**
* **Mineralisation-=** formation of solid calcium phosphate crystals
* **Osteocalcium phosphate ( brushite)-** also in bone
* serves as **reservoir 99% body's calcium, 85% phosphorous, 40-60% Na/K**
54
What is the composition of the organic matrix?
* **Collagen type 1 =90% of organic matrix**
* _triple helix of 2x alpha1 and 1x alpha2 chains_ with a repitive Gly XY sequence where glycine is the first position and X and Y are often proline/hydroxyproline arranged in a quarter staggered structural array-\> single fibrils
* responsible for the **tensile strength** of bone
* small amount of V and XI collagen
* **Bone specific proteoglycans**
* invovled in mineralisation/organistion of collagen fibres/binding of growth factors
* **Non collagenous matrix proteins**
* **Osteocalcin**
* **Osteonectin**
* **OSteopontin**
* **bone sialoprotein II**
* **Growth factors/cytokines**
* **BMP-17** ( members of transforming growth factor beta)
* **Insulin growth factor I** & **II**
* **Interleukins 1** &** 6**
55
What is Osteocalcin?
* produced by osteoblasts
* involved in control of osteoclasts
* gene on chromosome 1
56
What is Osteonectin?
* Secreted by Osteoblasts and platelets
* regulation of mineralisation
* gene on chromosome 5
57
What is osteopontin?
* A **non bone specific cell- binding protein anchoring osteoclasts to mineralised matrix**
* gene on chromosome 4
58
What is a good marker of bone turnover?
* **Hydroxyproline**
59
What is a good indiator of bone formation?
* Pro-collagen
* collagen telopeptides- carboxy-terminal
* bone specific alkaline phosphatase
* osteocalcin
60
What is a good indicator of bone breakdown?
* Pyridinoline and deoxypyridinoline
* X linkages formation beween adjacent triple helices are broken down
61
What is the blood supply to the bone?
* **Nutrient artery** system- (high pressure )
* **Metaphyseal- epiphyseal** system
* **Periosteal system** ( low pressure)
62
Describe the nutrient artery system?
* Major artery enters the mid-diaphysis thru a **nutrient foramen**
* once in medullary canal it divides into **ascending and descending arteries or arterioles** which anastomose with **metaphsyeal vessels** and directly penetrate the **endosteal surface supplying the inner 2/3rd cortex**
* in a child these vessels end on the metaphyseal side of the physis, contributing to process of endochondrl ossification
* at microscopic level, arterioles run in volkmann's canals with branches to the haversian systems, draining to venules and then into central venous sinus and out via the nutrient vein
63
Describe the metaphsyeal-epiphyseal system?
* Periarticular system complex penetrates the thin cortex and supplies the **metaphysis, physis and epiphysis.**
* **the metaphyseal vessels anatomose with the medullary and epiphyseal arteries after the growth plate fusion**
* in epiphysis with large articular surfaces such as radial and femoral heads, vessels enter the bone between articular cartilage and the physis, making the supply tenuous
64
Describe the periosteal system?
* Capillaries enter at the sites of major muscle attachments, normally supplying outer 1/3rd of teh cortex
* this is the domiant system in children- responsible for circumferential growth
*
65
what is the normal direction of blood fow in the bone?
* **Centrifugal**
* **ie inside to out**
66
What happens to bone blood flow after IM nailing?
* The endosteal blood suuply is damaged
* the **periosteal system becomes dominant **
* so the flow -\> **Centripetal = out to in**
* **venous blood system is normally centripetal**
